4.2.  IC
Starting in 2006, IC began reporting on its application of advanced epidemiological methods to support the GPEI as part of its collaboration with the World Health Organization (WHO). IC focused on statistical analyses of existing data and data collected as part of prospective clinical trials or challenge studies and did not perform any economic analyses. With respect to transmission modeling, between 2000 and 2019, IC applied dynamic transmission models to explore several specific topics. In 2013, using a simple DEB and SC model on two hypothetical populations, IC explored IPV use after OPV cessation, which suggested that IPV would protect children from paralysis, and under some conditions, IPV use could potentially limit transmission [97]. The study also noted that IPV use in routine immunization could also potentially delay the detection of outbreaks and allow transmission to spread further by preventing AFP cases [97]. In 2014, IC used an SC model to explore the impact of older age groups on the transmission of polioviruses, which identified faster outbreak response as substantially more important than expanding the age range of campaigns [98]. IC applied the same SC model in 2017 to explore a statistical inference framework to epidemiological and genetic data collected during a poliovirus outbreak to estimate transmission parameters [99]. Using an SC model for Nigeria, in 2016 IC characterized the role of tOPV SIAs before OPV2 cessation and suggested that in closed populations with no routine immunization coverage, conducting tOPV SIAs with some characteristics (e.g. one SIA with low coverage) could increase cVDPV2 risks after OPV2 cessation [100]. The inclusion of low routine immunization coverage in the model suggested the need for a sufficient number of focused tOPV SIAs before OPV2 cessation in areas at risk of VDPV2 emergence to raise population immunity above the transmission threshold [100].
IC also used statistical models to characterize transmission dynamics. Using data from Nigerian nonpolio AFP cases, IC applied a Poisson mixed effects model to characterize the connections between local government areas (LGAs) and suggested that a radiation model of human mobility provided the best fit [101]. IC applied a similar model to data from Pakistan and found that movement dynamics did not provide strong predictors for future cases and highlighted the necessity of improved SIA quality [102].
IC performed multiple case–control studies that estimated the efficacy of poliovirus vaccines using nonpolio AFP surveillance data collected by the GPLN, many of which supported GPEI decisions to introduce additional poliovirus vaccine formulations (e.g. mOPV1, bOPV, IPV) as new tools that would accelerate eradication. The first case–control study published by IC estimated the efficacy of tOPV vaccine in India, with a focus on areas with high population density and poor sanitation (i.e. Uttar Pradesh and Bihar) in which poliovirus transmission remained endemic [82]. This analysis showed poor tOPV efficacy per dose in these areas and suggested that using some mOPV1 SIAs in these areas could help to stop WPV1 transmission without significantly increasing WPV3 risks [82]. Subsequent case–control studies estimated vaccine efficacy of mOPV1 on the order of three times higher for serotype 1 poliomyelitis disease than for tOPV for Uttar Pradesh and Bihar [83] and for polio-endemic areas in northwest Nigeria [84]. Building on this work, IC led a challenge study in northern India to assess mucosal immunity induced by OPV, which demonstrated significant differences by location, serotype, vaccine formulation, and the number of doses [85]. IC assessed rates of excretion of live polioviruses (wild and OPV-related) in asymptomatic children in contact with suspected cases as a function of age, OPV doses received, and characteristics of the suspected case, which confirmed some asymptomatic participation in WPV transmission by OPV-vaccinated children [86]. Following the introduction of mOPV1 and mOPV3 in SIAs in Nigeria, IC compared the clinical characteristics of reported polio cases, estimated vaccine efficacy for different OPV vaccine formulations, and highlighted the improvements in vaccine-induced immunity against serotypes 1 and 3 and the decline in immunity to serotype 2 in children 0–2 years of age, which resulted in increased observations of cases caused by cVDPV2s [87]. IC explored the duration of mucosal immunity induced by OPV in India and suggested that it wanes significantly within 1 year [88].
Following the introduction of bOPV, in 2012, IC performed a case–control study using data from young children in Pakistan and Afghanistan that reported comparable effectiveness of bOPV to mOPV1 for serotype 1 and commented on the poor and declining immunization coverage in these countries [89]. In 2014, IC reported on the results of trials in India that demonstrated that the delivery of a supplemental IPV dose to previously-OPV-vaccinated children <5 years old boosted their intestinal immunity [90], and does so more effectively than a supplemental OPV dose [91]. Following this study cohort, in 2017 IC reported that the duration of boosting by IPV of intestinal immunity in OPV-vaccinated children remained elevated for 6 and 11 months, but showed evidence of waning [103]. Using data from Nigeria, in 2014 IC explored the vaccine effectiveness for the different formulations of OPVs in use (i.e. mOPVs, bOPV, tOPV) and suggested that immunity in children <3 years old to serotypes 1 and 3 had improved with the use of mOPVs and bOPV [92]. In 2016, using data from Indian infants 5–11 months old, IC reported that the number of tOPV doses received represented the main determinant of serotype 3 seropositivity [104], and reported results from a clinical trial that suggested that a 3-day course of azithromycin prior to delivery did not improve the immunogenicity of mOPV3 [105]. In 2018–19, using this same population, IC reported findings that showed a correlation between the quantity of virus shed and the magnitude of the serum neutralizing antibody response at 21 or 28 days [106], showed a greater impact on OPV response by enteric viruses than bacterial microbiota [107], and that did not show an association between seroconversion from one dose of mOPV3 and FUT2 genotype (i.e. single-nucleotide polymorphisms G428A, C302 T, and A385 T) [108].
In addition to analyzing results from clinical trials and challenge studies, IC also developed statistical models to characterize risks and effectiveness of some interventions by analyzing available data. In 2011, to explore the widespread transmission of WPVs in Africa, IC applied a statistical model that identified the proximity to the continued transmission in Nigeria and poor performance of national immunization programs in some neighboring countries as risk factors for transmission of reintroduced WPVs in Africa [93]. In 2017, IC revisited this topic for both Africa and Asia, concluded that low population immunity represented a key risk factor for WPV or cVDPV transmission, and recommended maintenance or improvement of vaccination in the high-risk areas it identified [109]. In 2015, IC applied a statistical model to estimate the effectiveness of SIAs using nonpolio AFP cases reported for children <2 years old in Pakistan, which showed temporal changes in coverage and identified some under-vaccinated populations [110]. Building on this work, in 2016 IC characterized spatial and temporal trends in vaccine-induced population immunity for serotype 2 for Nigeria and Pakistan prior to OPV2 cessation to explore the need for additional serotype 2-containing vaccines [111]. In 2016, using retrospective surveillance data, IC suggested that developing a real-time database of notified AFP cases and applying a Poisson space-time scan statistic at weekly intervals could potentially lead to earlier outbreak response [112]. In 2017, a year after OPV2 cessation IC analyzed the surveillance data and concluded that high population immunity prior to OPV2 cessation facilitated the die out of serotype 2 OPV-related viruses in most areas, but that cVDPV2 circulation continued in areas at high risk for transmission [113]. IC also performed a statistical analysis that explored the impacts of using IPV in addition to OPV for outbreak response in Pakistan and Nigeria and suggested some benefit of using IPV although the results were not statistically significant [114] and an updated analysis for Pakistan in 2018 [115]. In 2018, IC analyzed different sources of routine immunization data in Pakistan that showed both variable data quality and heterogeneous coverage [116] and assessed the sensitivity of poliovirus surveillance (both AFP and ES) for serotype 1 [117].
Between 2000 and 2019, IC also contributed a number of reviews to the literature. Recognizing the wealth of studies published over decades, IC systematically reviewed the OPV challenge studies that evaluated the induction of immunity from OPV and/or IPV against shedding, which concluded that immunization with IPV would likely show limited impact on poliovirus transmission in countries characterized by fecal-oral poliovirus transmission [94]. IC discussed some of the challenges for the polio endgame with a focus on issues related to OPV vaccine failure [95], results of clinical trials performed by others that added IPV to routine immunization schedules in OPV-only using countries [118, 119] including potential impacts of IPV on mucosal immunity [120], and showing no benefits of adding IPV in mOPV2 outbreak response SIAs [121]. IC also commented on biological challenges that limit the effectiveness of vaccines in the developing world, including OPV [122], and the need for innovation in poliovirus surveillance, vaccines, and vaccination strategies [123]. IC also systematically reviewed IPV vaccine effectiveness studies [96] and the impact of IPV on mucosal immunity [124], and suggested that IPV use could play a key role in halting poliovirus transmission and hasten polio eradication due to boosting of immunity of individuals previously given OPV [124]. IC also systematically reviewed the characteristics of known iVDPVs [125], interventions to improve oral vaccine performance [126], and the effect of different vaccine schedules on humoral and intestinal immunity against poliovirus [127].